tbuckley/cabot-search huggingface dataset:
PB1913: SYNERGISTIC EFFECTS OF DECITABINE AND APR-246 IN TP53 P.248Q-MUTATED MYELODYSPLASTIC SYNDROME
Authors: Y. Fang, C.-K. Chang
Journal: HemaSphere (2022)

Background: Mutations of TP53 gene confers inferior prognosis in myelodysplastic syndromes. Decitabine (DAC) has been used as the cornerstone drug for MDS treatment. However, less than half of MDS patients maintain a long-term response to DAC, and the maintenance time is usually less than one year. Aims: It is of great importance to reveal the therapeutic response mechanism of DAC to TP53-mutated MDS, explore related targets of DAC with short remission period, and optimize combined targeted therapy. Methods: We investigated the effect of small molecule inhibitor of TP53 mutation (APR-246) in combination with decitabine on the proliferation of MDS/AML cells (SKM-1, NB4 and KASUMI-1) which carries the recurrent homozygous TP53 mutation p.R248Q (TP53p.248Q). We further explore the associated mechanisms of combination therapy. Results: We found DAC combined with APR-246 had a synergistic effect on tumor cells with TP53p.248Q mutation in vitro. DAC activated a series of endogenous retroviruses (ERV) and upregulated TLR3 which activated anti-tumor immunity by promoting IFN-α secretion. However, IKK phosphorylation was also increased and induced NF-κB activation. Interestingly, this side-effect can be suppressed by APR-246, thereby synergistically promoting apoptosis of tumor cells. Summary/Conclusion: These results provided important evidence on optimizing existing therapeutic strategies for MDS/AML with TP53p.248Q.
PB2076: PEDIATRIC-TYPE FOLLICULAR LYMPHOMA - A NEW PARADIGM IN DIAGNOSIS?
Authors: L. Fonseca, C. Marques, H. Barroca, J. Lobo, R. Henrique
Journal: HemaSphere (2022)

Background: Recognized as an entity in the 2016 WHO Classification of Tumors of Hematopoietic and Lymphoid Tissues, Pediatric-Type Follicular Lymphoma (PTFL) is a rare nodular follicular lymphoma that affects primarily children and young adults. The clinical presentation is characterized by the sudden appearance of an isolated lymphadenopathy, with a predilection for the head and neck region, without systemic symptoms. The incidence is higher in men. It has an excellent prognosis with the excision of the affected ganglion. By definition, diagnosis is histological, immunocytochemical and molecular. There are no known risk factors or any described association with immunodeficiency or viral infections. Aims: We report two clinical cases. Methods: Case 1 - a previously healthy 18-year-old boy with an isolated, non-painful, cervical lymphadenopathy of approximately 20 mm, which was incidentally found. Case 2 – a 13-year-old boy without relevant personal history, who, after the second dose of vaccination against COVID-19, developed multiple adenomegalies that spontaneously regressed. However, one month later, a right submandibular adenomegaly appeared. It was analysed by ultrasound and was described as suspicious. In both cases, a fine-needle lymph node biopsy was performed for cytological diagnosis and material was sent for immunophenotyping by flow cytometry and molecular cytogenetics by FISH. Results: Immunophenotyping suggested a large-cell B-lymphoma with a phenotype compatible with Burkitt’s Lymphoma (BL). In the cytology of both cases, the population observed was more consistent with diffuse large B cell lymphoma (DLBCL) or possibly high-grade follicular lymphoma (FL). In the FISH study, no rearrangements in the MYC, BCL2, BCL6 or IRF4 genes were detected in the samples of the two cases. The lymphadenopathies were excised with a probable diagnosis of PTFL or DLBCL. Histological examination confirmed the PTFL diagnosis. Summary/Conclusion: We did not find in the literature any reference to clear causal relationship between vaccination against COVID-19 and the onset of lymphoproliferative diseases. The cytological/immunophenotypic/molecular approach of this entity in both cases seems to define a characteristic pattern, which may eventually allow, in a first approach, to suspect this diagnosis. More extensive studies will be needed to establish the role of these methodologies in the diagnosis of this pathology.
PB1802: ACUTE PROMYELOCYTIC LEUKEMIA AND THROMBOSIS: HOW TO IDENTIFY THE HIGH-RISK PATIENTS?
Authors: M. `Ben Salah, M. Bchir, R. Berred, R. Kharrat, Y. Ben Abdennebi, L. Aissaoui, R. Ben Lakhal, H. Ben neji, B. Meddeb
Journal: HemaSphere (2022)

Background: Acute promyelocytic leukemia (APL) is frequently associated with a disseminated intravascular coagulopathy (DIC), leading to severe bleeding complications. It's thus a diagnostic and therapeutic emergency. Nevertheless, the thrombotic risk is not to be neglected and is an interesting issue to highlight. Aims: The aim of this study was to describe the thromboembolic events (TE) associated with APL and to evaluate the associated clinical and biological factors. Methods: We conducted a retrospective single-center study that included patients diagnosed with APL between 2010 and 2019 in our department, treated with all-trans retinoic acid (ATRA) and anthracycline. Descriptive data related to the TE was collected. In order to identify the risk factors of TE, univariate and multivariate analysis were performed. Results: This study included 90 patients. A TE occurred in 10 patients (11%), with a median age of 48 years [20-62 years], and a sexe-ratio of 1. None had a previous history of thrombosis. Cardiovascular risk factors were found in 5 patients with TE (50%). An arterial TE developed in half of the cases: 2 had cerebrovascular accident (CVA, 20%), 2 had pulmonary embolism (PE, 20%), and 1 had myocardial infarction (MI, 10%). The venous TE encompassed deep vein thrombosis (DVT, 40%), and Budd-Chiari syndrome (10%). The TE was an initial symptom of APL for 4 patients (40%). It occurred during induction, and consolidation for 4 and 2 patients respectively. None of these patients had a differentiation syndrome or severe bleeding at the time of the TE. DIC was present in 2 patients (20%). As potential predictors of TE, we analyzed the following parameters: gender, age, Body Mass Index, cardiovascular risk factors, white blood cell (WBC) count greater than 10 G/L, hemoglobin (Hb), platelet count, fibrinogen less than 2g/l, prothrombin time (PT) less than 60%, DIC at diagnosis, Sanz score, cytological type, presence of CD2, CD15, additional cytogenetic abnormalities, PML-RARa variant, and the occurrence of a differentiation syndrome during induction. The following parameters were related to a statistically significant higher incidence of TE: Cardiovascular risk factors (p=0,011; 50% vs 29%), PT < 60% (p=0.02; 72% vs 32.5%), differentiation syndrome during induction (p=0.05; 40% vs 15%). The independent risk factors of TE, identified through the multivariate analysis, were: age (p=0.015, HR=7.7, IC 95%: [1.5 – 40]), and PT < 60% (p=0.019, HR= 7.5, IC95% [1.4 – 40.3]). Summary/Conclusion: The occurrence of TE in APL is a risk that should not be underestimated. The therapeutic strategy remains a challenge to overcome due to the associated DIC and thrombocytopenia. A better understanding of the risk factors is crucial to improve the management and the outcome of TE. Would a prophylaxis strategy be beneficial for APL patients with high risk of thrombosis?
One Health surveillance of West Nile and Usutu viruses: a repeated cross-sectional study exploring seroprevalence and endemicity in Southern France, 2016 to 2020
Authors: Orianne Constant, Patricia Gil, Jonathan Barthelemy, Karine Bolloré, Vincent Foulongne, Caroline Desmetz, Agnès Leblond, Isabelle Desjardins, Sophie Pradier, Aurélien Joulié, Alain Sandoz, Rayane Amaral, Michel Boisseau, Ignace Rakotoarivony, Thierry Baldet, Albane Marie, Benoît Frances, Florence Reboul Salze, Bachirou Tinto, Philippe Van de Perre, Sara Salinas, Cécile Beck, Sylvie Lecollinet, Serafin Gutierrez, Yannick Simonin
Journal: Eurosurveillance (2022)

Background West Nile virus (WNV) and Usutu virus (USUV), two closely related flaviviruses, mainly follow an enzootic cycle involving mosquitoes and birds, but also infect humans and other mammals. Since 2010, their epidemiological situation may have shifted from irregular epidemics to endemicity in several European regions; this requires confirmation, as it could have implications for risk assessment and surveillance strategies. Aim To explore the seroprevalence in animals and humans and potential endemicity of WNV and USUV in Southern France, given a long history of WNV outbreaks and the only severe human USUV case in France in this region. Methods We evaluated the prevalence of WNV and USUV in a repeated cross-sectional study by serological and molecular analyses of human, dog, horse, bird and mosquito samples in the Camargue area, including the city of Montpellier, between 2016 and 2020. Results We observed the active transmission of both viruses and higher USUV prevalence in humans, dogs, birds and mosquitoes, while WNV prevalence was higher in horses. In 500 human samples, 15 were positive for USUV and 6 for WNV. Genetic data showed that the same lineages, WNV lineage 1a and USUV lineage Africa 3, were found in mosquitoes in 2015, 2018 and 2020. Conclusion These findings support existing literature suggesting endemisation in the study region and contribute to a better understanding of USUV and WNV circulation in Southern France. Our study underlines the importance of a One Health approach for the surveillance of these viruses.
P1679: GENETIC POLYMORPHISM OF PLASMA HEMOSTATIC FACTORS AND THE RISK OF DEEP VEIN THROMBOSIS IN ELDERLY AND SENILE PATIENTS
Authors: A. Chechulova
Journal: HemaSphere (2022)

Background: Hereditary thrombophilia is a risk factor for venous thrombosis (VT) at young age. However, the risk of VT in patients older than 60 years is greatly increasing. The role of hereditary risk factors in development of VT in elderly and senile patients has not been studied enough. Aims: To assess the role of genetic variations in several plasma hemostatic factors in development of deep vein thrombosis (DVT) in elderly and senile patients. Methods: We examined 76 patients (37 men, 39 women) over 60 years of age with acute episode of DVT. Patients with cancer were excluded from the study. All the patients were divided into two age-dependent groups according to the WHO classification: elderly (60-74 years old), n=67 (78.4%) and senile (75-90 years old), n=9 (21.6%). The control group (CG) consisted of 191 healthy persons without a history of thrombotic episodes. Genotyping for DNA polymorphism of 8 genes encoding plasma hemostatic factors was performed by PCR-RFLP: fibrinogen α- and β-subunits (Thr312Ala and −455 G/A, respectively), FII (20210 G/A), FV (1691 G/A), FXII (46 C/T), FXIII A-subunit (Val34Leu), PAI-1 (−675 4G/5G), TPA (311 bp Ins/Del). Intergroup differences in genotypes distribution were assessed by Fisher’s exact test. The odds ratios (OR) with their 95% confidence intervals (CI) and p-values were determined by using the SPSS statistical package (version 23.0; SPSS Inc, Chicago, IL, USA). Results: The frequencies of heterozygous genotypes FV 1691 GA and FII 20210 GA were 3.8 and 3.5 times higher in DVT patients than in the CG (14.5% vs. 4.4%; OR=3.8; 95% CI: 1.5–9.7; p=0.004 and 5.3% vs. 1.6%; OR=3.5; 95% CI: 0.7–15.6; p=0.098, respectively). Homozygotes for the FII 20210 G/A mutation were not found in any group, and the FV 1691 AA variant was present in 1 (1.3%) patient with DVT. The heterozygous FXIII 34 Val/Leu variant was underrepresented in DVT group (32.9% vs. 47.7% in CG; OR=0.5; 95% CI: 0.3–0.9; p=0.03), whereas the genotype FXIII 34 Val/Val was prevalent among DVT patients (61.8% vs. 47.1% in CG; OR=1.9; 95% CI: 0.9–3.1; p=0.03). No differences were found between the compared groups for other genetic variants. However, when comparing patient groups depending on age, heterozygotes for the FV 1691 G/A (22.2% vs. 13.4%; OR=1.8; 95% CI: 0.3–10.3; p=0.58) as well as for the α- and β-subunits of fibrinogen (66.7% vs. 37.3%; OR=3.4; 95% CI: 0.7–14.5; p=0.093 and 44.4% vs. 28.4%; OR=2.0; 95% CI: 0.5–8.3; p=0.23, respectively) were more prevalent in senile patients. In contrast, heterozygotes for the TPA Ins/Del polymorphism were almost 4 times more common in elderly patients with DVT (40.3% vs. 11.1% in senile patients; OR=5.4; 95% CI: 0.7–45.3; p=0.089). Summary/Conclusion: The heterozygous genotype FV 1691 GA as well as the FXIII 34 Val/Val variant are associated with increased VTE risk in elderly and senile patients from North-Western Russia.
PB1960: M6A-REGULATED LNCRNA SNHG15 MODULATES HISTONE H3K36ME3 METHYLATION AND HETEROCHROMATIN REDISTRIBUTION IN MULTIPLE MYELOMA
Authors: Y. Lan, H. Mei, L. Tingting, Y. Hua, W. Qiuling
Journal: HemaSphere (2022)

Background: Our previous results indicated that the m6A demethylase ALKBH5 acted on lncRNA SNHG15 in multiple myeloma and positively regulated its expression. LncRNA SNHG15 was highly expressed in CD138 + plasma cells from MM Patients and MM cell lines. The overexpression of lncRNA SNHG15 in ALKBH5-knockdown cells rescued the inhibited cell proliferation, the suppressed cell migration, and the accelerated cell apoptosis. Fatherly, we preliminarily found that ALKBH5 regulated histone H3K36me3 modification through SNHG15. Aims: We aim to further display the potential molecular mechanisms between ALKBH5 regulated-lncRNA SNHG15 and histone-related heterochromatin involved in the progression of MM. Methods: The expression of lncRNA SNHG15, SETD2, Histone 3 and H3K36me3 were detected by RT-qPCR and western blot. SNHG15-siRNA lentivirus SNHG15L1-cNDA lentivirus and NC were transfected into MM cells to knock-down and knock-in lncRNA SNHG15 gene. Chromatin Immunoprecipitation sequencing (CHIP-seq) and CHIP-qPCR were previously accomplished (the results have not yet been published). Heterochromatin protein-1 alpha (HP1-α) IF (Immunofluorescence) staining was used to show the distribution of heterochromatin. Results: ALKBH5, lncRNA SNHG15 and SETD2 are all overexpressed in MM primary cells and cell lines, associating with poor prognosis, especially renal injury. Through overexpressing lncRNA SNHG15 in MM PMI8226 ALKBH5- cells, we display that lncRNA SNHG15 rescued the inhibited cell proliferation, the suppressed cell migration, and the accelerated cell apoptosis caused by ALKBH5 knockdown. Western blot analysis reveals the expression changes of histone H3K36me3 methyltransferase SETD2 among control, ALKBH5-, ALKBH5-SNHG15+ group MM RPMI8226 cells. Heterochromatin protein-1 alpha (HP1-α) IF (Immunofluorescence) staining exhibited the heterochromatin redistribution following ALKBH5 knock-down and lncRNA SNHG15 Knock-in. CHIP-seq uncovered that cellular H3K36me3 level has been showed no significant difference, but a redistribution existed in groups above. Besides, Enrichment analysis and western blot experiments revealed that ALKBH5/lncRNA SNHG15 axis mediated cell adhesion/migration through CDH4/CDH9 associated β-catenin signal pathway. CHIP-qPCR verified that the enrichment of H3K36me3 on CDH4 gene body altered following ALKBH5 knock-down and lncRNA SNHG15 Knock-in. Summary/Conclusion: The ALKBH5/lncRNA SNHG15 axis promotes myelomagenesis and cell migration through β-catenin/CDH4 signal pathway. m6A-regulated lncRNA SNHG15 alters H3K36me3 distribution and modulates heterochromatin through upregulating SETD2 expression in MM cells. SETD2 is overexpressed in MM primary cells and cell lines, associating with poor prognosis.
Phylogenomic characterization and signs of microevolution in the 2022 multi-country outbreak of monkeypox virus
Authors: Joana Isidro, Vítor Borges, Miguel Pinto, Daniel Sobral, João Dourado Santos, Alexandra Nunes, Verónica Mixão, Rita Ferreira, Daniela Santos, Silvia Duarte, Luís Vieira, Maria José Borrego, Sofia Núncio, Isabel Lopes de Carvalho, Ana Pelerito, Rita Cordeiro, João Paulo Gomes
Journal: Nature Medicine (2022)

The largest monkeypox virus (MPXV) outbreak described so far in non-endemic countries was identified in May 2022 (refs.
PB2335: BURDEN OF HOSPITALIZATION, COSTS AND CO-MORBIDITIES IN MEDICAID PATIENTS WITH SICKLE CELL DISEASE (SCD): ANALYSIS OF NATIONAL IN-PATIENT HOSPITAL DATABASE
Authors: S. Aggarwal, S. Kumar, H. Topaloglu, A. Bela, O. Topaloglu
Journal: HemaSphere (2022)

Background: Sickle cell disease (SCD) is a group of inherited red blood cell disorders. SCD affects approximately 100,000 Americans. Aims: To analyze trends in hospital length of stay, total costs and co-morbidities in Medicaid patients with Sickle Cell Disease (SCD). Methods: The National Inpatient Sample (NIS) data set from the Healthcare Cost and Utilization Project was utilized in order to determine the number of hospital admissions for Sickle Cell Disease (SCD). Thirty co-morbidities were assessed using Elixhauser scoring. The outcomes assessed include length of stay (LOS), total charges, co-morbidity score, mortality rate and emergency room visits. The SCD ICD-10 codes used were ‘D57.0’, ‘D57.1’, ‘D57.2’, ‘D57.4’ and ‘D57.8’. Results: There were an estimated 125,405 hospitalizations with a diagnosis of SCD, of which 53% were covered by Medicaid. The mean age was 24.17 (SD 13, Median was 24) years and 53% of the patients were female. The mean hospital length of stay for Medicaid patients with SCD was 5 (SD 6.48, Median was 3 days). The mean hospital charges were $36048 (SD $58044). The mean comorbidity score was 1.33 (SD 1.53). The in-hospital mortality rate was 0.3%. The vast majority of the patients were Black (91%), Hispanic (5%) and White (1%). The top five listed co-morbid conditions were were Chronic Pulmonary Disease (26%), Fluid and Electrolyte Disorders (18%), Hypertension (11%), Drug Abuse (11%) and Depression (9%). The second most common listed diagnosis was for asthma (J45909). The top procedure codes were for blood transfusion and Infusion Device into Superior Vena Cava. Approximately, 79% of Medicaid patients were admitted to the hospital via the emergency room visit. Summary/Conclusion: Medicaid patients with Sickle Cell Disease pose significant burden on hospitals with relatively long length of stay. Due to comorbidities of COPD, asthma and drug abuse, these patients might need special treatment management to improve overall outcomes.
P948: INCIDENCE AND CLINICAL OUTCOME OF SARS-COV-2 INFECTION AFTER VACCINATION IN PATIENTS WITH MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS)
Authors: N. Sgherza, P. Curci, R. Rizzi, D. Roccotelli, M. Croce, M. Avantaggiato, L. Ruga, A. Vitucci, A. Palma, D. Di Gennaro, P. Musto
Journal: HemaSphere (2022)

Background: Our group recently reported that MGUS patients investigated during the early waves of pandemic, when vaccines were still not available, neither have an increased risk of contracting SARS-CoV-2, infection, nor show poorer COVID-19 outcomes with respect to healthy controls (Sgherza N. et al. Haematologica. 2022). Aims: Aiming to specifically address the clinical effects of vaccines, we compared incidence and outcome of SARS-CoV-2 infection of 1,454 previously described, not vaccinated MGUS patients (91 of whom were SARS-CoV-2 positive), with those observed in a similar population during the national vaccination campaign. Methods: We obtained retrospective information from 86 individuals found to be SARS-CoV-2 positive among 1,265 MGUS patients analyzed after at least two doses of anti-SARS-CoV-2 vaccine received between April 2021, and January, 2022. Seventy-one subiects positive before vaccination or after only one dose were escluded from analysis. Results: The mean age of this group was 65.7 +/- 13.3 years (range 31-90); 32 patients were female (37%), and 54 were male (63%). About MGUS-subtypes, the most frequent one was IgG-kappa (n=35; 40.7%), followed by IgG-lambda (n=28; 32.5%), IgM-kappa (n=11; 12.8%) and others (n=12; 14%). Most of patients (81/46, 94.2%) were at low or low-intermediate risk, according to Mayo Clinic prognostic model. Thirty-seven (43%) patients developed SARS-CoV-2 infection after two doses (9, 26 and 2 patients receiving ChAdOx1-S, BNT162b2 mRNA and mRNA-1273 vaccines, respectively), fourty-nine (57%) after three doses (BNT162b2 mRNA or mRNA-1273 as “booster” dose, repectively). The mean number of days between last dose of vaccine and SARS-CoV-2 infection was 103.04 +/-80.28 (range 2-285). The two populations of SARS-CoV2 positive MGUS patients (before and after vaccination) were comparable for age, sex and presence of co-morbidities (data not shown). Overall, rates of symptoms (59.3% vs 26.7%), hospitalization (20.9% vs 2.3%), hospitalization in Intensive Care Unit (11% vs 1.2%) and rate of deaths (8.8% vs 1.2%) were significantly higher in still not vaccinated MGUS patients than in those who had received vaccines (Table 1). Image:Summary/Conclusion: Our data indicate that the incidence of SARS-CoV-2 infection is not significantly reduced in fully vaccinated MGUS patients (even after three doses), likely also because of the higher diffusion capacity of the recently recognized Omicron viral variants. However, as observed in normal population and in other hematological contexts, the clinical outcome of COVID-19 may be significantly improved after vaccination in these patients, with symptoms present in less of one third of subjects and no case of hospitalization or death in our series. These observations support extensive vaccination programs in patients with MGUS.
P1024: IMPACT OF TP53 IN MYELOFIBROSIS UNDERGOING STEM CELL TRANSPLANTATION
Authors: N. Gagelmann, A. Badbaran, V. Panagiota, C. Wolschke, F. Ayuk, F. Thol, M. Ditschkowski, B. Cassinat, M. Robin, T. Schroeder, M. Heuser, H. C. Reinhardt, N. Kröger
Journal: HemaSphere (2022)

Background: Most of myelofibrosis (MF) cases harbor somatic mutations in the driver genes JAK2, CALR, or MPL. Other somatic nondriver mutations have been increasingly detected with the use of high-throughput sequencing. The role of TP53 in prognosis of MF has long been unclear, but recent first studies suggested worse survival for patients harboring this mutation. Aims: While allogeneic stem cell transplantation still remains the only curative treatment option, outcome of patients with TP53 has not been evaluated yet. Methods: Here, we analysed in 417 patients with PMF or post ET/PV MF incidence and impact on otcome of TP53. We detected 46 patients with detectable TP53 mutation using next-generation sequencing, and compared characteristics and outcome after allograft with 371 non-TP53 patients with primary or secondary MF. Samples were collected at time of transplantation. Primary end points were overall survival (OS) and nonrelapse mortality. Secondary objectives were relapse, relapse-free survival, and graft-versus-host disease (GVHD). Results: Median follow-up from transplantation was 6.1 years for the TP53 group and 7.0 years for the non-TP53 group, respectively (P=0.50). Baseline characteristics were generally balanced, whereas more patients in the TP53 group had Karnofsky performance score <90 (57% versus 40%; P=0.04). Median OS was 2.1 years (0.1-5.4 years) for the TP53 group versus 15.4 years (11.5-19.3 years) for the non-TP53 group (P=0.002), and the 6-year OS was 40% (24-55%) for the TP53 group versus 65% (60-70%) for the non-TP53 group. 6-year nonrelapse mortality was 35% (21-49%) for the TP53 group versus 27% (22-32%) for the non-TP53 group (P=0.16) and 6-year incidence of relapse was 26% (13-39%) for the TP53 group versus 18% (14-21%) for the non-TP53 group (P=0.09). 6-year relapse-free survival was 35% (20-50%) versus 53% (48-58%; P=0.01). Acute GVHD occurred in 63% versus 57% (P=0.43). Of patients with relapse, 92% in the TP53 group versus 63% in the non-TP53 group died (P=0.05). Risk for death appeared to be associated with variant allele frequency (P=0.06). Summary/Conclusion: MF patients with TP53 appeared to have higher nonrelapse mortality and relapse incidence but significantly worse relapse-free and overall survival, mainly because of worse survival after relapse.